Compounds of this general type are known in the art, but not as antiinflammatory agents or as agents to treat dysmenorrhea. A number of references including J. L. Melles and H. J. Backer, Rec. trav. chim., Vol. 72, 314 (1953), and S. Hauptmann and E. -M. Werner, J. prakt. Chem., Vol. 314, 499 (1972), disclose the preparation of 2,3-diphenylthiophene.
Melles and Backer, op. cit., describe the preparation of 2-bromo-3,4-diphenylthiophene; 4,5-dibromo-2,3-diphenylthiophene; 3,5-dibromo-2,4-diphenylthiophene; and 3,4-dibromo-2,5-diphenylthiophene. U.S. Pat. No. 4,174,405 describes 2-halo-3,5-diarylthiophenes and their use as acaricides.
U.S. Pat. No. 4,302,461 issued to Cherkofsky on Nov. 24, 1981, generically and broadly discloses compounds of the formula ##STR1## where Y can be either H or Br, as members of a reaction sequence to produce alkylthio substituted thiophenes useful as antiinflammatory agents. No intrinsic utility or biological activity is disclosed for the compounds pictured above.
In addition, the synthesis of the preferred 2-trifluoromethylthio and 2-trifluoromethylsulfonyl substituted compounds of the U.S. Pat. No. 4,302,461 patent utilizes trifluoromethanesulfenyl chloride which is extremely toxic [Chemical & Engineering News, Vol. 45, 44 (1967)]. In contrast, the compounds of the instant invention are made utilizing relatively non-toxic bromine as a reagent.
U.S. patent application Ser. No. 354,300 filed Mar. 3, 1982, by Haber discloses compounds of the formula, ##STR2## where Y can be F, Cl, Br, or I, but does not claim any composition of matter containing bromine. Three of the four compounds claimed in the instant application are disclosed on page 4 of U.S. Ser. No. 354,300 as specifically preferred in view of their outstanding activity.
There is a continuing need for safe and effective antiinflammatory agents. Inflammation is a disease process characterized by redness, fever, swelling, and pain. Arthritis, in its various forms, is the most prevalent, chronic, and severe of the inflammatory diseases. Traumatic injury and infection also involve inflammation, and antiinflammatory drugs are often used in their treatment. The usefulness of most commercial antiinflammatories is limited, however, because of toxicity and adverse side-effects. Many produce gastric irritation and other effects, such as changes in blood cells and in the central nervous system. Adrenocortical steroids produce gastric irritation and suppression of normal adrenal function.
Dysmenorrhea is a painful condition associated with menstruation which affects an estimated 30-50 percent of women of childbearing age causing the loss of more than 140 million working hours per year [J. L. Marx, Science, Vol. 205, 175 (1979)]. The symptoms of dysmenorrhea include nausea, vomiting, diarrhea, and headache. Abnormally high levels of prostaglandin compounds occur in the endometrium and menstrual fluid of patients suffering from primary dysmenorrhea. Prostaglandins are known to cause uterine contractions, sensitize nerve endings to pain, and cause the typical symptoms of the condition. Treatment of dysmenorrhea with prostaglandin synthetase inhibitors reduces prostaglandin levels and relieves the symptoms of dysmenorrhea [M. R. Henzl and A. Izu, Acta. Obstet. Gynecol. Scand. Suppl., Vol. 87, 105-117 (1979) and W. Y. Chan, M. Y. Dawood, and F. Fuchs, Am. J. Obstet. Gynecol., Vol. 135, 102-108 (1979)].
There is thus a clear need for improved antiinflammatory agents, especially ones which also possess activity as prostaglandin synthetase inhibitors which would be independently useful for treatment of dysmenorrhea.